Volume 134, Issue 3 , Pages 601-607, September 2007
Neurologic outcomes of thymectomy in myasthenia gravis: Comparative analysis of the effect of thymoma
Article Outline
Objectives
The objectives of this study were to compare the clinical features and the outcomes after thymectomy between patients with and without thymoma and to evaluate the influence of thymectomy on the subsequent clinical course of myasthenia gravis.
Methods
Between 1995 and 2003, 64 consecutive patients underwent thymectomy, and of these, 60 patients were followed up for at least 12 months postoperatively. The study population was divided into 2 groups based on the presence of thymoma. We performed a retrospective analysis to compare the neurologic outcomes of thymectomy between patients with thymomatous myasthenia gravis and those with nonthymomatous myasthenia gravis.
Results
Twenty-four patients had a thymoma. No significant differences were observed between the 2 groups regarding the preoperative severity of myasthenia gravis. There was no significant difference in the follow-up duration between the 2 groups. There was no significant difference in the overall remission rate between the 2 groups (P = .064). The mean time required to reach a remission was 10.6 months and 23.5 months in the thymoma and nonthymoma groups, respectively. The mean duration of remission was 43.1 months and 30.8 months in the thymoma and nonthymoma groups, respectively. In the early phase of follow-up, more patients reached remission in the thymoma group than those in the nonthymoma group (P = .040).
Conclusions
Neurologic outcomes of the thymoma group were no worse than those of the nonthymoma group. It is expected that earlier thymectomy is likely to result in a better prognosis by shortening the disease period, even for patients with nonthymomatous myasthenia gravis.
CTSNet classification: 13
Abbreviations and Acronyms: CT, computed tomography, MG, myasthenia gravis, MGFA, Myasthenia Gravis Foundation of America
Myasthenia gravis (MG) is an autoimmune disorder that is caused by an antibody-mediated attack directed against acetylcholine receptors at the neuromuscular junction. Thymoma occurs in 24% to 38% of patients with late-onset MG.1, 2 Both the clinical severity of MG and the outcomes after thymectomy are different between the patients with and those without thymoma. Thymoma is considered a poor prognostic factor of MG because of either the more severe symptoms or the less responsiveness to treatment.3, 4, 5, 6, 7, 8, 9, 10
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Thymoma may be a source of autoantigen in thymomatous MG, and therefore we hypothesized that the myasthenic symptoms of patients with thymoma would have better response to thymectomy than would those of patients without thymoma. The objectives of this study were to compare the clinical features and their outcomes after thymectomy between patients with and those without thymoma and to evaluate the influence of thymectomy on the subsequent clinical course of MG.
Materials and Methods
Between January 1995 and December 2003, 64 consecutive patients with a diagnosis of MG underwent thymectomy at our institution. Of these, 60 patients were followed up for at least 12 months postoperatively, and they constituted the study population. Their medical records were retrospectively reviewed to compare the clinical characteristics and long-term results between the patients with thymoma and those without thymoma, and we focused on the neurologic outcomes of MG. The study was reviewed and approved by the Institutional Review Board of the Sungkyunkwan University.
The diagnosis of MG was primarily based on the clinical features and confirmed by 1 or more of the following tests: the positive tensilon test, the repetitive nerve stimulation test, and assay for acetylcholine receptor antibody. All the patients underwent computed tomographic (CT) scanning of the chest to ascertain whether they had pathologic abnormalities of the thymus. The severity of MG was retrospectively evaluated at the time of diagnosis, during the period of medical management, and immediately before the operation according to the clinical classification of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (MGFA).11
Thymectomy was recommended when either thymoma or hyperplasia of the thymus was detected on the CT scan or when the patients aged 19 through 69 years had generalized symptoms of MG. All thymectomies were performed transternally, as described previously, and every possible effort was made to eliminate all the thymic tissue as completely as possible.7 A consistent protocol of perioperative care was used, including preoperative stabilization and postoperative management of the patients.
A histopathologic examination was performed on all specimens and then reviewed by a pathologist. Thymomas were histologically classified based on the new World Health Organization classification of Rosai and Sabin as type A (medullary), AB (mixed), B1 (organoid), B2 (cortical), B3 (epithelial), or C (thymic carcinoma) thymoma. For the patients with thymoma, pathologic staging was done according to the scheme suggested by Masaoka and colleagues.12 Stage I was defined as macroscopically completely encapsulated thymomas, with no microscopically determined capsular invasion; stage II was defined as macroscopic invasion into the surrounding fatty tissue or mediastinal pleura or microscopic invasion into capsule; stage III was defined as macroscopic invasion into neighboring organs (ie, pericardium, great vessels, and lung); stage IVa was defined as pleural or pericardial dissemination; and stage IVb was defined as lymphogenous or hematogenous metastasis. Patients with advanced stages of thymoma received adjuvant radiation therapy or both adjuvant radiation therapy and chemotherapy.
All the patients were regularly followed up at intervals of 3 months for the first 2 years postoperatively and then every 6 months thereafter. A detailed report of the MGFA classification and medications for each patient was obtained at every point of follow-up and then reviewed by a neurologist. The clinical outcomes regarding MG were classified according to the MGFA postintervention status11: complete stable remission, pharmacologic remission, improved, unchanged, and worse. The remission rate was defined as the ratio of the number of patients in either complete or pharmacologic remission to the number of patients whose information concerning the neurologic status was available at each follow-up visit. A follow-up CT scan was performed to rule out the possibility of a recurrent thymic tumor in patients with sustained neurologic symptoms.
The study population was divided into 2 groups based on the presence of a thymoma. Descriptive statistics were used to describe the patients’ characteristics and outcomes. The normally distributed continuous data were expressed as means ± SD. Categoric data were expressed as counts and proportions. The Student t test and the χ2 or Fisher exact test were used to compare the continuous and categoric variables, respectively.
Results
Patient Profile
The clinical characteristics and operative techniques of the study population are presented in Table 1. Twenty-four (40%) patients turned out to have a thymoma. The thymoma group consisted of 8 men and 16 women with a mean age of 46.5 ± 15.3 years. The nonthymoma group was comprised of 10 men and 26 women with a mean age of 36.4 ± 11.5 years. The mean duration of preoperative symptoms was 2.0 ± 5.0 months for the patients with thymoma compared with 22.0 ± 27.3 months for those without thymoma. No significant differences were observed between the thymoma group and the nonthymoma group regarding the severity of MG immediately before the operation. The preoperative antiacetylcholine receptor antibody titer was 7.5 ± 3.2 nmol/L and 6.6 ± 4.2 nmol/L in the thymoma and nonthymoma groups, respectively. In the nonthymoma group, 16 (44.4%) patients required immunosuppression therapy preoperatively, whereas 5 (20.8%) patients of the thymoma group received immunosuppression therapy before their operations.
Table 1. Clinical characteristics of the study population
| All patients n = 60 | Thymoma (+) n = 24 | Thymoma (−) n = 36 | P value | |
|---|---|---|---|---|
| Age at diagnosis, y (mean ± SD) | 39.3 ±14.3 | 46.4±15.2 | 34.6±11.7 | .003 |
| Age at operation, y (mean ± SD) | 40.5±14.0 | 46.5±15.3 | 36.4±11.5 | .009 |
| Male sex/female sex | 18/42 | 8/16 | 10/26 | .645 |
| Duration of symptoms, n (%) | .002 | |||
| ≤1 y | 45(75) | 23(96) | 22(61) | |
| >1 y | 15(25) | 1(4) | 14(39) | |
| MG classification, n (%) | .121 | |||
| Ocular | 16(27) | 9(38) | 7(19) | |
| Generalized | 44(73) | 15(62) | 29(81) | |
| MGFA stage, n (%) | .824 | |||
| I | 16(27) | 9(38) | 7(19) | |
| IIa | 17(28) | 4(17) | 13(36) | |
| IIb | 22(37) | 8(33) | 14(39) | |
| IIIa | 1(2) | 1(4) | — | |
| V | 4(7) | 2(8) | 2(6) | |
| MGFA stage (mean ± SD) | 2.0±0.9 | 1.9±1.1 | 2.0±0.8 | .826 |
| Myasthenic crisis, n (%) | 6(10) | 3(13) | 3(8) | .675 |
| Preoperative remission, n (%) | 2(3) | 0(0) | 2(6) | .512 |
| AChR Ab, nmol/L (mean ± SD) | 6.9±3.9 | 7.5±3.2 | 6.6±4.2 | .412 |
| Immunosuppressants, n (%) | 21(35) | 5(21) | 16(44) | .060 |
Operative Results
There was no in-hospital mortality. No patients experienced significant complications related to the operation. Of the 24 patients who underwent thymectomy for both MG and thymoma, 4 (16.7%) were treated for myasthenic crisis postoperatively, whereas none of the patients without thymoma experienced myasthenic crisis. The postoperative antiacetylcholine receptor antibody titer was 7.6 ± 3.7 nmol/L and 6.5 ± 4.2 nmol/L in the thymoma and nonthymoma groups, respectively. A report of the pathologic findings was available for all the patients, which revealed hyperplasia of the thymus in 26 patients, thymoma in 24 patients, thymolipoma in 3 patients, fatty involution of the thymus in 2 patients, and normal thymus in 1 patient. Among the 24 patients who had both MG and thymoma, 13 (54.2%) had stage I disease, 7 (29.2%) had stage II disease, 3 (12.5%) had stage III disease, and 1 (4.2%) had stage IV disease. Except for the 1 patient with pleural dissemination, there was no incomplete resection of the thymoma. Thirteen (54.2%) patients received adjuvant therapy for either invasive thymoma or thymic carcinoma. There were no recurrences of thymic tumors, except for the 1 patient with stage IV thymic carcinoma. A repeat operation was not performed in any group. The histologic classification of the specimens and the pathologic staging of thymoma are listed in Table 2.
Table 2. Histologic classification and pathologic staging of thymoma
| WHO classification, n (%) | |
| B1 | 5(20.8) |
| B2 | 9(37.5) |
| B2 + B3 | 2(8.3) |
| B3 | 7(29.2) |
| C | 1(4.2) |
| Masaoka stage, n (%) | |
| I | 13(54.2) |
| II | 7(29.2) |
| III | 3(12.5) |
| IV | 1(4.2) |
Neurologic Outcomes
Follow-up was completed for all the patients, with a mean duration of 58.1 months (range, 15.4-133 months). There was no significant difference in the follow-up duration between the 2 groups. During follow-up, 23 (95.8%) patients in the thymoma group achieved an asymptomatic state, as did 29 (80.6%) in the nonthymoma group, regardless of the length of the symptom-free period. In the thymoma group 16 (66.7%) patients were asymptomatic at the last follow-up, and of these, 11 needed no medication for MG. In the nonthymoma group 24 (66.7%) patients were asymptomatic at the last follow-up, and of these, 21 required no medication for MG. Among the thymoma group, 18 (75%) patients experienced either complete or pharmacologic remission during the follow-up period. Of these, 12 patients maintained the remission until the last follow-up visit, whereas 6 had a relapse. On the other hand, among the nonthymoma group, 25 (69.4%) patients reached either complete or pharmacologic remission before the last follow-up visit. Of these, 20 patients remained in remission, whereas 5 relapsed thereafter. There was no significant difference in the remission rates between the 2 groups (P = .064). The time required to reach a remission was 10.6 ± 9.7 months and 23.5 ± 30.6 months in the thymoma and nonthymoma groups, respectively (P = .059). The mean duration of remission was 43.1 ± 27.3 months and 30.8 ± 21.1 months in the thymoma and nonthymoma groups, respectively (P = .151). The remission rate of the thymoma group at 1, 2, 3, 4, and 5 years was 54.2%, 60.9%, 66.7%, 61.1%, and 61.5%, respectively (Figure 1). The remission rate of the nonthymoma group at 1, 2, 3, 4, and 5 years was 30.6%, 32.1%, 39.1%, 42.9%, and 41.2%, respectively (Figure 1). There were no significant differences in the remission rates between the 2 groups, except for the 2-year rate (P = .040). The data regarding the neurologic outcomes during the follow-up period are summarized in Table 3. Comparisons of the MGFA class and the percentages of asymptomatic or generalized patients with MG with all the patients are shown in Figure 2, Figure 3, Figure 4.
Figure 1.
Comparison of the remission rates between the thymoma and nonthymoma groups.
Table 3. Neurologic outcomes after thymectomy
| All patients n = 60 | Thymoma (+) n = 24 | Thymoma (−) n = 36 | P value | |
|---|---|---|---|---|
| FU duration, mo (mean ± SD) | 58.1 ± 28.5 | 63.0 ± 23.4 | 54.8 ± 31.6 | .280 |
| ASx during FU, n (%) | 52(87) | 23(96) | 29(81) | .128 |
| Myasthenic crisis, n (%) | 4(7) | 4(17) | — | .022 |
| Last FU visit, n (%) | ||||
| Asymptomatic | 40(67) | 16(67) | 24(67) | 1.000 |
| Ocular MG | 8(13) | 3(13) | 5(14) | 1.000 |
| Generalized MG | 12(20) | 5(21) | 7(19) | 1.000 |
| Remission rate (%) | ||||
| Overall | 72 | 75 | 69 | .064 |
| At 1 y | 40 | 54 | 31 | .067 |
| At 2 y | 45 | 61 | 32 | .040 |
| At 3 y | 52 | 67 | 39 | .068 |
| At 4 y | 51 | 61 | 43 | .256 |
| At 5 y | 50 | 62 | 41 | .269 |
| TuR, mo (mean ± SD) | 18.1±24.8 | 10.6±9.7 | 23.5±30.6 | .059 |
| DoR, mo (mean ± SD) | 36.0±27.5 | 43.1±27.3 | 30.8±27.1 | .151 |
| Relapse, n (%) | 11(26) | 6(33) | 5(20) | .321 |
| Final outcomes, n (%) | .903 | |||
| CR | 23(38) | 8(33) | 15(42) | |
| PR | 9(15) | 4(17) | 5(14) | |
| Improved | 16(27) | 9(38) | 7(19) | |
| Unchanged | 8(13) | 1(4) | 7(19) | |
| Worse | 4(7) | 2(8) | 2(6) | |
| AChR Ab, nmol/L (mean ± SD) | 6.9±4.0 | 7.6±3.7 | 6.5±4.2 | .371 |
Figure 2.
Comparison of the Myasthenia Gravis Foundation of America (MGFA) class between the thymoma and nonthymoma groups.
Figure 3.
Comparison of the percentages of patients with generalized myasthenia gravis (MG) between the thymoma and nonthymoma groups.
Figure 4.
Comparison of the percentages of asymptomatic patients between the thymoma and nonthymoma groups.
Discussion
The relationship between MG and the thymus has been recognized for a number of years, because the thymus in patients with MG often shows pathologic abnormalities, such as thymic follicular hyperplasia and thymic tumors. Epithelial tumor of the thymus (ie, thymoma) occurs in approximately 10% of patients with MG, and in turn, MG occurs in approximately 15% of patients with thymomas.13 When patients with MG also have a thymoma, their clinical manifestations are significantly distinct from those seen in the patients without thymomas. In comparison with patients without thymomas, the onset of MG in patients with thymomas tends to be late, with a peak incidence in the sixth and seventh decades, and this combined disease mostly affects men.5 Likewise, in our practice patients with MG with thymoma were older than those without thymoma, and men were more frequently affected in the thymoma group than in the nonthymoma group.
Since Blalock and associates14 reported a remission of generalized MG after removal of a thymic tumor in 1939, numerous studies have demonstrated the favorable outcomes of thymectomy on the natural course of the disease, and thymectomy is currently considered to be effective for treating MG.15 Many studies have been conducted to determine the prognostic factors of thymectomy, and a variety of prognostic predictors have been identified, including age at operation,6, 9, 10, 12, 16, 17, 18 the severity of MG,10, 16, 19 and the preoperative duration of symptoms.3, 6, 7, 10 Among these, the presence of thymoma indicates a poor prognosis after thymectomy for MG.3, 4, 5, 6, 7, 8, 9, 10 Jaretzki and coworkers4 found a decreased remission rate and increased mortality among patients with thymomas and MG. Masaoka and associates,12 in their large study of 375 patients, observed that 67.2% of the patients without thymomas achieved remission at 15 years compared with 31.8% of the patients with thymomas. They suggested that the absence of thymoma was one of the favorable prognostic factors.
In our study, however, we found that patients with thymomas appeared to have better neurologic outcomes after thymectomy than did those without thymomas. In the early phase of follow-up, and especially 2 years after the operation, considerably more patients reached a remission state in the thymoma group than in the nonthymoma group (P = .040). The longer the duration of follow-up, the less was the difference in the remission rates between the 2 groups, with the long-term results of the nonthymoma group showing improvement. Nevertheless, the thymoma group showed at least no less favorable outcomes than did the nonthymoma group, even in the late phase. The overall remission rate of the thymoma group was no lower than that of the nonthymoma group (75% vs 69%, P = .064). Additionally, not only did the patients with thymoma reach a remission earlier (10.6 vs 23.5 months, P = .059) but they also maintained it longer (43.1 vs 30.8 months, P = .151) than did those without thymomas. Despite this tendency, however, there was no statistically significant difference between the 2 groups. When the patients who achieved remission were followed up, there were no significant differences in the relapse rates between the 2 groups. Our findings seem to be quite different from the previous series in the literature, which regarded the presence of a thymoma as a poor prognostic factor.
These results could be interpreted from several perspectives. First, when the patients have both MG and thymoma, the overall prognosis could be influenced by invasiveness of the tumors, as well as by the neurologic symptoms. Most of the patients in the thymoma group in our series had less advanced stages of tumor, which could have had less of an adverse effect on the prognosis of MG.
Second, it has been reported that patients with thymoma tend to have more advanced MG preoperatively, and some authors speculated that the poor outcomes for patients with thymomatous MG could be explained by this tendency. In our practice the severity of neurologic symptoms in the thymoma group was no more advanced than that in the nonthymoma group, and this might have led to better results in the thymoma group, which is in contrast to the past reports.
Third, it is likely that patients with thymomas undergo thymectomy earlier than those without thymomas. When myasthenic patients are also given a diagnosis of thymoma, prompt thymectomy is recommended for the treatment of a thymoma per se. Neurologists or physicians could easily decide to suggest an operation for patients with both MG and thymoma. On the contrary, when there is no evidence of a thymic tumor, then there could be a propensity to postpone a thymectomy or to continue medical treatment. In our study 23 of 24 patients with thymoma underwent thymectomy within a year after a diagnosis of MG, whereas 14 of 36 patients without thymoma had to have MG for more than a year before their operations. Given that the short duration of preoperative symptoms has been consistently considered a good prognostic factor in most series,3, 6, 7, 10 the reason why the patients with thymoma showed relatively favorable outcomes in our series could be that they received thymectomy almost immediately after diagnosis. In the same context the patients without thymoma would have achieved much better outcomes if thymectomy had been recommended as early as was done for the patients with thymoma.
This study demonstrated different results than did those of the previous reports, and we tried to interpret the implications of our findings. Nonetheless, we could not reveal the mechanism of dissimilar responses to thymectomy between the thymoma and nonthymoma groups. It is generally known that thymomatous MG is distinct from nonthymomatous MG as to the pathogenesis of disease. However, it is still unclear how a thymoma plays a role for patients with MG, although it has been assumed that a thymoma could be the substantial source of continued antigenic stimulation. Had we performed antibody assay for various antigens other than the acetylcholine receptor, it would have been helpful to elucidate the differences between the 2 groups. In addition, because our data were retrospectively gathered and then analyzed, this study has important limitations. Furthermore, the study population was rather too small to show the significant difference in neurologic outcomes between the thymoma and nonthymoma groups, and there were few cases for which the relationship between relapse of MG and recurred thymoma could be investigated. If the patients had experienced recurrence of thymoma after a remission and then they had been followed by the relapse of MG, this would have been strong evidence that MG was provoked by a thymoma.
In conclusion, we evaluated the influence of thymomas on the results of thymectomy for patients with MG by comparing the neurologic outcomes between the thymoma and nonthymoma groups. Neurologic outcomes of the thymoma group were no worse than those of the nonthymoma group. It is expected that earlier thymectomy is likely to result in a better prognosis by shortening the disease period, even for patients with nonthymomatous MG. We believe that it is necessary to perform a prospective study under clinical circumstances that would include antibody assays for the various antigens specific to thymomas, and thymomatous MG should be considered a different disease category from nonthymomatous MG.
References
- . The thymus in myasthenia gravis. Neurol Clin. 1994;12:331–342
- . The thymus in myasthenia gravis. Ann N Y Acad Sci. 1993;681:47–55
- Effects of thymectomy in myasthenia gravis. Ann Surg. 1987;206:79–88
- “Maximal” thymectomy for myasthenia gravis (Results). J Thorac Cardiovasc Surg. 1988;95:747–757
- . The natural course of myasthenia gravis: a long term follow-up study. J Neurol Neurosurg Psychiatry. 1989;52:1121–1127
- . Actuarial analysis of the occurrence of remissions following thymectomy for myasthenia gravis in 400 patients. J Neurol Neurosurg Psychiatry. 1991;54:406–411
- Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac Surg. 1996;62:853–859
- Prognosis of myasthenia gravis: a retrospective study of 380 patients. J Neurol. 1997;244:548–555
- . Prognostic factors of thymectomy in patients with myasthenia gravis: a cohort of 132 patients. Eur Neurol. 2001;46:171–177
- . Predictors of outcome in thymectomy for myasthenia gravis. Ann Thorac Surg. 2001;72:197–202
- Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000;55:16–23
- . Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48:2485–2492
- . Studies in myasthenia gravis: review of twenty-year experience in over 1200 patients. Mt Sinai J Med. 1971;38:497–537
- . The treatment of myasthenia gravis by removal of the thymus gland. JAMA. 1941;117:1529–1531
- . Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:7–15
- Transsternal radical thymectomy for myasthenia gravis: a 15-year review. Ann Thorac Surg. 1989;47:838–840
- Thymectomy for the myasthenia gravis patient: factors influencing outcome. Ann Thorac Surg. 1994;57:334–338
- Thymectomy for myasthenia gravis: a 27-year experience. Eur J Cardiothorac Surg. 1999;15:621–625
- Prognostic factors for myasthenic gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg. 1999;67:1568–1571
Supported by the Samsung Medical Center Clinical Research Development Program grant, CRS 104-32-2.
PII: S0022-5223(07)00876-8
doi:10.1016/j.jtcvs.2007.05.015
© 2007 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Volume 134, Issue 3 , Pages 601-607, September 2007